Treatment of hospital acquired, ventilator-associated, and healthcare-associated pneumonia in adults

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Treatment of hospital-acquired, ventilator-associated, and
healthcare-associated pneumonia in adults
Author Section Editor Deputy Editor
Thomas M File, Jr, MD John G Bartlett, MD Anna R Thorner, MD

Last literature review version 19.1: enero 2011 | This topic last updated: febrero 17, 2011
INTRODUCTION — Hospital-acquired (or nosocomial) pneumonia (HAP), ventilator-associated
pneumonia (VAP), and healthcare-associated pneumonia (HCAP) are important causes of morbidity
and mortality despite improved antimicrobial therapy, supportive care, and prevention [1].

The treatment of HAP, VAP, and HCAP will be reviewed here. The diagnosis, epidemiology,
pathogenesis, microbiology, risk factors, and prevention of HAP, VAP, and HCAP are discussed
separately. (See "Clinical presentation and diagnosis of ventilator-associated pneumonia" and
"Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired, ventilator-associated,
and healthcare-associated pneumonia in adults" and "Risk factors and prevention of hospital-acquired,
ventilator-associated, and healthcare-associated pneumonia in adults".)

DEFINITIONS

Pneumonia types — The 2005 ATS/IDSA guidelines distinguish the following types of pneumonia
[2]:

Hospital-acquired (or nosocomial) pneumonia (HAP) is pneumonia that occurs 48 hours or more
after admission and did not appear to be incubating at the time of admission.

Ventilator-associated pneumonia (VAP) is a type of HAP that develops more than 48 to 72 hours
after endotracheal intubation.

Healthcare-associated pneumonia (HCAP) is defined as pneumonia that occurs in a
non-hospitalized patient with extensive healthcare contact, as defined by one or more of the
following:

Intravenous therapy, wound care, or intravenous chemotherapy within the prior 30 days
Residence in a nursing home or other long-term care facility
Hospitalization in an acute care hospital for two or more days within the prior 90 days
Attendance at a hospital or hemodialysis clinic within the prior 30 days

The guidelines can be accessed through the ATS web site at http://www.thoracic.org/statements/.

Multidrug resistance — The definition of multidrug resistance (MDR) in gram-negative bacilli, which
are an important cause of HAP, VAP, and HCAP is variably defined as resistance to at least two, three,
four, or eight of the antibiotics typically used to treat infections with these organisms [3].
Extensively-drug resistant (XDR) gram-negative bacilli are defined by resistance to all commonly used
systemic antibiotics except colistin, tigecycline, and aminoglycosides.

Panresistance refers to those gram-negative organisms with diminished susceptibility to all of the
antibiotics recommended for the empiric treatment of VAP, including cefepime, ceftazidime,

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imipenem, meropenem, piperacillin-tazobactam, ciprofloxacin, and levofloxacin. (See 'Empiric
treatment' below.)

Risk factors for multidrug resistance are discussed separately. (See "Epidemiology, pathogenesis,
microbiology, and diagnosis of hospital-acquired, ventilator-associated, and healthcare-associated
pneumonia in adults", section on 'MDR risk factors'.)

TREATMENT — Appropriate antibiotic therapy significantly improves survival for patients with HAP,
VAP, or HCAP [2,4]. However, establishing the diagnosis of pneumonia in such patients can be
difficult, especially those on mechanical ventilation in whom clinical, radiologic, and microbiologic
findings can be due to numerous etiologies besides pneumonia. The difficulty in diagnosis may lead to
overtreatment with its attendant risks of superinfection and antibiotic toxicity. (See "Clinical
presentation and diagnosis of ventilator-associated pneumonia".)

When therapy is given, antimicrobial selection should be based upon risk factors for MDR pathogens,
including recent antibiotic therapy (if any), the resident flora in the hospital or ICU, the presence of
underlying diseases, and available culture data (interpreted with care). For patients with risk factors
for multidrug-resistant (MDR) pathogens, empiric broad-spectrum, multidrug therapy is
recommended. Once the results of pretherapy cultures are available, therapy should be narrowed
based upon the susceptibility pattern of the pathogens identified.

The importance of providing appropriate therapy at the time of presentation was illustrated in a
retrospective study of almost 400 patients with culture-positive HCAP who survived but remained
hospitalized 48 hours after hospital admission [5]. Mortality was significantly higher among the 107
patients who received inappropriate initial therapy compared with the 289 patients who received
appropriate coverage (30 versus 18 percent); switching to an appropriate regimen did not reduce the
risk of death.

In a study that assessed the microbial prediction and validated the adequacy of the 2005 American
Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines for HAP in the ICU,
adherence to the guidelines resulted in more adequate treatment and a trend toward a better clinical
response in patients who presented late (≥5 days) or had risk factors for drug-resistant bacteria, but
did not affect mortality [6]. The 2005 guidelines were worse than the 1996 guidelines for predicting
drug-resistant bacteria; this was mostly observed for cases classified as lower risk for multidrug-
resistant pathogens (ie, early onset infection without specified risk factors for resistant infection),
suggesting that such patients may in fact be at risk for resistant pathogens.

In a later observational study that included 303 patients at risk for MDR pathogens, 28-day mortality
was higher among patients who were treated according to the ATS/IDSA guidelines compared with
patients whose treatment did not comply with the guidelines (34 versus 20 percent) [7]. The primary
reason for “non-compliance” was lack of a second drug for gram-negative pathogens. Criticisms of this
study include the observation that lower coverage for certain MDR pathogens occurred in the
compliant group (but was not commented upon by the authors), lack of assessment of the impact of
timing of antimicrobial therapy, lack of appropriate adjustment for risk of death, disregard of the
impact of treatment de-escalation on the classification of compliance, and the possibility that excess
mortality may have been at least partly due to toxicity when a triple regimen is used [8]. In addition,
although the authors attempted to control for higher severity of infection observed in the compliant
group, the results may still have been confounded by patients in the compliant group who were at
greater risk of poor outcomes at presentation. Potential messages from this study are: clinicians who
are following patients and are aware of pathogen and susceptibility patterns within a specific unit may
be better able to appropriately select empiric therapy based on individual clinical judgment rather
than using routine combination therapy (guidelines are meant to supplement clinical judgment, not
supplant judgment); the need for two-drug therapy is not necessary in many cases of gram-negative

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infection; and the definition of risk for MDR as stated in the 2005 guidelines is not precise,
particularly for HCAP, and should be readdressed. (See 'Gram-negative pathogens' below and
'Multidrug resistance' above.)

A retrospective study showed that HCAP is associated with more severe disease, longer hospital stay,
and higher mortality rates than CAP, and that the use of antimicrobial therapy not recommended by
the ATS/IDSA guidelines was associated with increased mortality in such patients [9]. Another
observational study found that lack of adherence to a VAP protocol (which included considerations of
appropriate use and duration of antibiotics) resulted in longer duration of therapy, ventilation, and
length of ICU stay [10].

In a retrospective analysis of local microbiologic data on HAP pathogens from 111 consecutive
patients in 2004, investigators developed institution-specific treatment guidelines in order to improve
empiric antibiotic therapy [11]. Institution guideline-directed treatment regimens were predicted to
provide adequate initial therapy for >90 percent of patients who develop HAP ≥10 days after
hospitalization (eg, those at greatest risk of multidrug resistant pathogens). In this institution, use of
a fluoroquinolone per the national guidelines, would not have provided adequate additional
antimicrobial activity for the beta-lactam resistant gram-negative bacilli (ciprofloxacin was active
against <10 percent of these pathogens which were also resistant to piperacillin-tazobactam and
cefepime). This study illustrates the importance of using local susceptibility data to develop treatment
guidelines.

The implementation of recommendations to assess a patient's status 72 hours after the initiation of
therapy and to discontinue antibiotics or narrow the regimen (deescalate therapy) based upon
appropriate culture results may reduce the selective pressure for antimicrobial resistance.

A prospective observational study of 398 intensive care unit (ICU) patients with suspected VAP found
that mortality was significantly lower among patients in whom therapy was deescalated compared to
those whose therapy was either escalated or unchanged (17 versus 43 and 24 percent, respectively)
[12]. The study was limited because of its observational nature; confirmation of these results awaits a
randomized controlled study. In another study, deescalation was evaluated in surgical patients with
septic shock in a retrospective evaluation of 138 patients with VAP [13]. Deescalation of antimicrobial
therapy occurred in 55 percent of patients who had received initial therapy effective against the
identified pathogen (most common initial choice was vancomycin plus piperacillin-tazobactam). The
mortality rate of patients who underwent deescalation therapy was 35 percent compared with 42
percent among patients who did not have deescalation, a difference that did not reach statistical
significance. This study demonstrated that deescalation therapy did not lead to recurrent pneumonia
or increased mortality in this population of critically ill surgical patients.

There has been interest in the nonantibiotic antiinflammatory effects of macrolides. A randomized
trial of 200 patients with sepsis and VAP showed that those who received clarithromycin (in addition
to standard treatment including antibiotics) had significantly faster resolution of VAP (10 versus 15.5
days) and weaning from mechanical ventilation (16 versus 22.5 days) compared to those who
received placebo [14]. Among those who died of sepsis, time to death was significantly prolonged in
those who received clarithromycin.

Specific antimicrobial considerations — In critically ill patients, in those receiving antibiotics prior
to the onset of pneumonia, and in institutions where these pathogens are frequent, coverage of
methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, and antibiotic-resistant
gram-negative bacilli, such as Acinetobacter spp, and Legionella should be considered.

MRSA — If MRSA is a frequent nosocomial pathogen in the institution, linezolid or vancomycin is a
necessary first choice for anti-staphylococcal coverage [2,15,16], but should be discontinued if MRSA
is not isolated.

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An overview of the treatment of invasive MRSA infections is presented separately. (See "Treatment of
invasive methicillin-resistant Staphylococcus aureus infections in adults".)

Linezolid and vancomycin — Several trials have compared linezolid and vancomycin, with
variable results. Two prospective, randomized trials of nosocomial pneumonia compared linezolid with
vancomycin; each found no significant difference in outcomes for MRSA infections [17,18]. A
subsequent open-label trial showed only a trend towards earlier microbiologic cure, clinical cure, and
survival rate among patients treated with linezolid for VAP compared with those treated with
vancomycin [19]. A meta-analysis of nine randomized trials that compared linezolid with vancomycin
(in seven trials) or teicoplanin (in two trials) for nosocomial pneumonia found no differences in rates
of clinical cure or microbiologic eradication [20]. In addition, no differences in clinical cure or
microbiologic eradication were observed in the subgroup analysis of patients with MRSA. However, in
a later randomized double-blind trial that compared linezolid to vancomycin for the treatment of
hospital-acquired pneumonia (HAP) or healthcare-associated pneumonia (HCAP) due to proven MRSA,
the end of study success rate was 58 percent for linezolid and 47 percent for vancomycin [21].
Linezolid was non-inferior and statistically superior to vancomycin in end of treatment clinical
outcome, and microbiologic outcome at end of treatment and end of study.

A retrospective study suggested that vancomycin failure might be related to suboptimal dosing [22].
As a result, a trough level of 15 to 20 mcg/mL is often targeted [2]. However, subsequent studies
failed to confirm that higher vancomycin trough concentrations correlate with improved outcomes
[23,24]. On the other hand, higher vancomycin MICs themselves may be associated with worse
outcomes in patients with HAP due to MRSA. This was suggested in a prospective cohort study of 95
patients with MRSA HCAP who were treated with vancomycin in which the targeted trough
vancomycin concentration was at least four times the MIC [23]. High MIC (≥2 mcg/mL) strains of
MRSA were detected in 54 percent of patients. Despite achieving the target trough concentration,
mortality was higher among patients whose MRSA strain had a high MIC than patients whose MRSA
strain had a low MIC (24 versus 10 percent). In a later prospective study that included 158 patients in
the ICU with HAP, VAP, or HCAP, an increase in 28-day mortality was observed in patients whose
MRSA isolates had increased MICs; an increase in mortality occurred as the vancomycin MIC
increased from 0.75 to 3 mcg/mL, and was present even for strains within the susceptible range [25].

The 2005 ATS/IDSA treatment guidelines on HAP, VAP, and HCAP, and a 2009 United States
pharmacy consensus review recommend target vancomycin trough concentrations of 15 to 20 mcg/mL
[2,26]. However, these recommendations are based on retrospective pharmacokinetic modeling in the
absence of prospective clinical data. PK/PD analysis has suggested that lung vancomycin AUC:MIC
>400 may be difficult to achieve (particularly for isolates with MIC >1) [27-29]. Clinical data have
failed to demonstrate a relationship between treatment outcome and target troughs of 15 to 20
mcg/mL [2]. (See "Vancomycin dosing and serum concentration monitoring in adults".)

The 2005 ATS/IDSA guidelines on HAP, VAP, and HCAP and the 2011 IDSA guidelines for the
treatment of MRSA infections recommended either linezolid or vancomycin for infections suspected or
proven to be due to MRSA [2,16]. It was noted that linezolid might be preferred in patients at risk for
or with renal insufficiency in whom vancomycin is often underdosed and is associated with a risk of
nephrotoxicity. Linezolid also may reduce toxin production, although the possible benefit of this has
not been established [30,31]. Linezolid is particularly preferred in hospitals in which a substantial
proportion of MRSA isolates have a vancomycin MIC ≥2 mcg/mL. Linezolid resistance and linezolid
failure have been described rarely. An alternative to linezolid and vancomycin is clindamycin (600 mg
IV or orally three times daily), provided that the isolate is known to be susceptible, although there are
fewer data to supports its use [16]. (See "Epidemiology of methicillin-resistant Staphylococcus aureus
infection in adults", section on 'Linezolid resistance' and "Treatment of invasive methicillin-resistant
Staphylococcus aureus infections in adults", section on 'Linezolid'.)

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The usual doses are:

Linezolid — 600 mg twice daily IV (or orally if or when the patient is able to receive oral
medications).

Vancomycin — 15 to 20 mg/kg (based on actual body weight) IV every 8 to 12 hours for
patients with normal renal function, with a target serum trough concentration of 15 to 20 mg/L
[26]. In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to facilitate rapid
attainment of the target trough concentration. (See "Vancomycin dosing and serum
concentration monitoring in adults".)

Telavancin — Telavancin is an intravenous semisynthetic lipoglycopeptide antibiotic that is
broadly active against both aerobic and anaerobic gram-positive bacteria, including streptococci,
methicillin-susceptible S. aureus, methicillin-resistant S. aureus (MRSA), and some vancomycin-
resistant enterococci [32]. In two randomized trials (the ATTAIN studies) that included 1503 patients
with HAP due to gram-positive bacteria, especially MRSA, telavancin (10 mg/kg IV daily) was
noninferior to vancomycin in terms of clinical response (58.9 percent versus 59.5 percent) [33].
Among patients with monomicrobial Staphylococcus aureus infection, the cure rates were higher in
patients who received telavancin, particularly among those with an MRSA isolate with reduced
susceptibility to vancomycin (MIC ≥1 mg/dL); the cure rate among patients with MRSA with reduced
susceptibility to vancomycin was 87 percent in those who received telavancin versus 74 percent in
those who received vancomycin. The cure rates were for all patients with monomicrobial MRSA
infection regardless of vancomycin MIC were 81.8 percent for telavancin and 74.1 percent for
vancomycin (95% CI -3.5-19.3). These results suggest that telavancin is particularly useful for
patients with MRSA isolates with a vancomycin MIC ≥1 mg/dL. However, telavancin has not been
approved by the US Food and Drug Administration for the treatment of pneumonia.

Although the overall incidence of adverse events was similar in the two groups, the incidence of
serious adverse events and/or adverse events leading to drug discontinuation was higher in the
telavancin group in both trials (31 versus 26 percent and 8 versus 5 percent, respectively). A
significant rise in serum creatinine (>50 percent from baseline and a maximum value >1.5 mg/dL)
was more common in the telavancin group than the vancomycin group (16 versus 10 percent).

Other agents — There has been interest in using other agents for the treatment of MRSA
pneumonia, but none of the following agents can be recommended:

Daptomycin cannot be used to treat pneumonia because it does not achieve sufficiently high
concentrations in the respiratory tract.

Data are limited on the use of quinupristin-dalfopristin. In a randomized trial of HAP that
included 38 patients with MRSA pneumonia, there was a nonsignificant lower rate of clinical
success with quinupristin-dalfopristin compared with vancomycin (31 versus 44 percent) and a
higher rate of adverse effects that led to discontinuation of therapy [34].

Ceftaroline is a broad-spectrum cephalosporin with activity against MRSA, which has been
approved for CAP, but not for staphylococcal pneumonia [35].

Tigecycline is a broad-spectrum antibiotic with activity against MRSA. In September 2010 the
FDA issued a safety announcement regarding increased mortality risk associated with the use of
tigecycline compared with that of other drugs that was observed in a pooled analysis of 13 trials
[36]. The increased risk was seen most clearly in patients treated for HAP, particularly VAP.

Gram-negative pathogens — Although combination antimicrobial therapy for HAP, VAP, and
HCAP due to gram-negative pathogens (especially Pseudomonas) is commonly administered, there is

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no conclusive evidence to support this practice. The best rationale for the use of combination therapy
is to provide a greater spectrum of activity when there is risk for MDR pathogens (eg, if the pathogen
is resistant to one agent it may be susceptible to the other) [2]. Other commonly cited reasons for
combination therapy include the potential for synergistic efficacy as well as the potential to reduce the
emergence of resistance. However, it is not clear that two agents offer improved outcomes for
treating gram-negative pneumonia.

A meta-analysis and a subsequent large, randomized trial suggested that monotherapy of VAP was as
effective as combination therapy [37,38]. However, the percentage of MDR organisms was low in the
trials reviewed in the meta-analysis and in the randomized trial. In addition, the randomized trial
excluded patients known to be colonized with Pseudomonas or MRSA, and found that combination
versus monotherapy was associated with improved adequacy of initial antibiotics and microbiological
eradication of infecting organisms in patients who had infection due to Pseudomonas, Acinetobacter,
and MDR gram-negative bacilli [38]. Thus, it is difficult to extrapolate the efficacy of monotherapy to
ICUs with high incidences of these pathogens.

In another study of patients hospitalized in an ICU due to trauma, 84 patients with VAP caused by
Pseudomonas were treated with monotherapy (cefepime 2 g intravenously every 8 hours); this
resulted in microbiologic eradication (based on repeat BAL showing <103 organisms/mL) in 94
percent of patients with no recurrences, suggesting that combination therapy is unnecessary when
the initial antimicrobial therapy is active against the isolate [39].

In ICU settings in which extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are
found, cephalosporins should be avoided as monotherapy, due to the selection of resistant organisms
when these agents are used [40]. The most reliable agent in this setting is a carbapenem (imipenem-
cilastatin, ertapenem, meropenem, or doripenem) [41-43].

Legionella — Patients who have diabetes mellitus, renal disease, structural lung disease, or have
been recently treated with glucocorticoids may require coverage for Legionella spp (azithromycin or a
fluoroquinolone). HAP and VAP due to Legionella spp are also more common in hospitals where the
organism is present in the hospital water supply. (See "Epidemiology and pathogenesis of Legionella
infection" and "Treatment and prevention of Legionella infection".)

Anaerobes — Patients who have aspirated or had recent abdominal surgery may warrant
coverage for anaerobes (clindamycin, beta-lactam-beta-lactamase inhibitor, or a carbapenem). (See
"Aspiration pneumonia in adults" and "Anaerobic bacterial infections", section on 'Pleuropulmonary
infections'.)

Empiric treatment — We generally agree with the American Thoracic Society/Infectious Diseases
Society of America (ATS/IDSA) guidelines for the management of HAP, VAP, or HCAP [2]. These
guidelines can be accessed through the ATS web site at http://www.thoracic.org/statements/.

No known MDR risk factors — We suggest one of the following intravenous antibiotic regimens
for empiric coverage of HAP, VAP, and HCAP in patients with no known risk factors for multidrug-
resistant (MDR) pathogens:

Ceftriaxone (2 g intravenously daily).

Ampicillin-sulbactam (3 g intravenously every six hours).

Levofloxacin (750 mg intravenously daily) or moxifloxacin (400 mg intravenously daily). When
the patient is able to take oral medications, either agent may be administered orally at the
same dose as that used for IV administration.

Ertapenem (1 g intravenously daily).

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Choice of a specific agent for empiric therapy should be based on knowledge of the prevailing
pathogens (and susceptibility patterns) within the healthcare setting. If there is concern for
gram-negative bacilli resistant to the above options (eg, Enterobacter spp, Serratia spp, Pseudomonas
spp) based upon microbiologic data at the specific institution, we feel that it is reasonable to initiate
piperacillin-tazobactam (4.5 g IV every six hours) or another agent (eg, cefepime or a carbapenem)
as monotherapy for patients without known risk factors for MDR bacteria provided that the
institution’s susceptibility data support in vitro activity.

Known MDR risk factors — Host risk factors for infection with multidrug resistant (MDR)
pathogens include receipt of antibiotics within the preceding 90 days, current hospitalization of ≥5
days, high frequency of antibiotic resistance in the community or in the specific hospital unit,
immunosuppressive disease and/or therapy, and presence of risk factors for HCAP. (See
"Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired, ventilator-associated,
and healthcare-associated pneumonia in adults", section on 'MDR risk factors'.)

For patients with known MDR risk factors, we recommend empiric combination therapy including:

ONE of the following:

Antipseudomonal cephalosporin such as cefepime (2 g intravenously every eight hours) or
ceftazidime (2 g intravenously every 8 hours)

Antipseudomonal carbapenem such as imipenem (500 mg intravenously every six hours) or
meropenem (1 g intravenously every eight hours) or doripenem (500 mg intravenously every
eight hours; administered over one hour for HAP or HCAP, administered over four hours for
VAP) [42,43]

Piperacillin-tazobactam (4.5 g intravenously every six hours)

For patients who are allergic to penicillin, the type and severity of reaction should be assessed.
The great majority of patients who are allergic to penicillin by skin testing can still receive
cephalosporins (especially third-generation cephalosporins) or carbapenems. If there is a history
of a mild reaction to penicillin (not an IgE-mediated reaction, Stevens Johnson syndrome or
toxic epidermal necrolysis), it is reasonable to administer a cephalosporin or carbapenem using
a simple graded challenge (eg, give 1/10 of dose, observe closely for 1 hour, then give
remaining 9/10 of dose, observe closely for 1 hour). Skin testing is indicated in some situations.
If a skin test is positive or if there is significant concern to warrant avoidance of a cephalosporin
or carbapenem, aztreonam (2 g intravenously every six to eight hours) is recommended.
Indications and strategies for skin testing are reviewed elsewhere. (See "Penicillin-allergic
patients: Use of cephalosporins, carbapenems, and monobactams".)

Patients with past allergic reactions to cephalosporins may also be treated with aztreonam, with
the possible exception of those allergic to ceftazidime. Ceftazidime and aztreonam have similar
side chain groups, and cross reactivity between the two drugs is variable. The prevalence of
cross-sensitivity has been estimated at <5 percent of patients, based upon limited data. Patients
with past reactions to ceftazidime that were life-threatening or suggestive of anaphylaxis
(involving urticaria, bronchospasm, and/or hypotension) should not be given aztreonam unless
evaluated by an allergy specialist. In contrast, a reasonable approach in those with mild past
reactions to ceftazidime (eg, uncomplicated maculopapular rash) would involve informing the
patient of the low risk of cross-reactivity and administering aztreonam with a graded challenge
(1/100, 1/10, full dose, each separated by 1 hour of observation). (See "Cephalosporin-allergic
patients: Subsequent use of cephalosporins and related antibiotics", section on 'Use of
carbapenems and monobactams'.)

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PLUS one of the following:

Antipseudomonal fluoroquinolone, preferred regimen if Legionella is likely, such as
ciprofloxacin (400 mg intravenously every eight hours) or levofloxacin (750 mg intravenously
daily). These agents may be administered orally when the patient is able to take oral
medications. The dose of levofloxacin is the same when given intravenously and orally, while
the dose of ciprofloxacin is 750 mg orally twice daily.

Aminoglycoside such as gentamicin or tobramycin (7 mg/kg intravenously once daily) or
amikacin (20 mg/kg intravenously once daily); once daily dosing is only appropriate for patients
with normal renal function. A single serum concentration should be obtained 6 to 14 hours after
the first dose, and the dose should be adjusted as needed based upon the following nomogram
(figure 1). The aminoglycoside can be stopped after five to seven days in responding patients.
(See "Consolidated aminoglycoside dosing with gentamicin and tobramycin".)

PLUS ONE of the following (if MRSA is suspected, there are MRSA risk factors, or there is a high
incidence of MRSA locally):

Linezolid (600 mg intravenously every 12 hours; may be administered orally when the patient
is able to take oral medications)

Vancomycin (15 to 20 mg/kg [based on actual body weight] intravenously every 8 to 12 hours
for patients with normal renal function, with a target serum trough concentration of 15 to 20
mg/L.) In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to facilitate rapid
attainment of the target trough concentration. (See "Vancomycin dosing and serum
concentration monitoring in adults".)

If patients have recently received antibiotics, empiric therapy should generally be with a drug from a
different class since earlier treatment may have selected pathogens resistant to the initial class.

Because of increasing resistance of pathogens associated wth VAP, HAP, and HCAP, one potential
strategy to enhance the antimicrobial potential of a given agent is to optimize the pharmacodynamic
effect. Since the beta-lactams are associated with optimal outcomes when the level of the drug is
above the minimum inhibitory concentration (MIC) for the pathogen for an appropriate percent of the
dosing interval, this effect can potentially be improved with prolonged infusion of the antimicrobial.
This has been demonstrated with the use of a 3 to 4 hour infusion of piperacillin-tazobactam,
cefepime, or the carbapenems for the treatment of VAP due to gram-negative bacilli with higher MICs
than the usual breakpoints for susceptibility [44-46].

Aerosolized antibiotics — Aerosolized colistin, polymyxin, or aminoglycosides may be
considered as potential additional antibiotics in patients with multidrug-resistant (MDR)
gram-negative bacilli [47-51]. Aerosolization may increase antibiotic concentrations at the site of
infection, and may be particularly useful for treatment of organisms that have high MICs to systemic
antimicrobial agents [52]. In a randomized trial that included 100 patients with VAP due to
gram-negative bacilli (predominantly MDR Acinetobacter baumannii and/or Pseudomonas aeruginosa),
patients who were treated with a combination of systemic antibiotics and nebulized colistin had a
higher rate of favorable microbiologic outcome compared with patients who were treated with
systemic antibiotics alone (microbiologic eradication or presumed eradication 61 versus 38 percent),
but there was no differences in clinical outcome (51 versus 53 percent) [51].

In a retrospective case-control study that included 86 patients with VAP due to MDR gram-negative
bacilli (predominantly A. baumannii) treated with a combination of IV and aerosolized
colistin compared with IV colistin alone, there was only a trend towards improved rates of clinical

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cure, pathogen eradication, and mortality in the patients who received aerosolized and IV colistin
[53]. However, this study may have been underpowered to show a benefit, adequate doses of
aerosolized colistin may not have been used, and the difficulty in diagnosing VAP may have biased the
results (ie, if patients without VAP were included) [54]. (See "Colistin: An overview".)

Antibiotic regimens — When the etiology of HAP, VAP, or HAP has been identified based upon
reliable microbiologic methods and there is no laboratory or epidemiologic evidence of coinfection,
treatment regimens should be simplified and directed to that pathogen. The choice of specific agents
will be dictated by the results of susceptibility testing. It is crucial to avoid broad-spectrum therapy
once a pathogen has been identified [2,8].

A novel approach may determine antimicrobial susceptibility more quickly than traditional methods.
In a trial, Gram stain was performed on endotracheal aspirates from 250 patients with
bacteriologically confirmed VAP [55]. The endotracheal aspirates whose Gram stain identified a
microbe were randomly assigned to either rapid testing — the endotracheal aspirates were directly
applied to antibiotic susceptibility test strips — or standard culture. Rapid testing more quickly
identified susceptibility than standard culture (1.4 versus 4.2 days). In addition, patients were more
likely to receive appropriate antimicrobial therapy, have fewer days of antimicrobial therapy, and
have more rapid resolution of fever. Antimicrobial selection based on this strategy has never been
compared to that based on a Gram stain or local susceptibility patterns. Nor has it been compared to
empiric broad spectrum therapy based on MDR risk factors. Until further clinical studies are
performed, this approach cannot be recommended in the routine management of HAP.

Patients who are improving clinically, are hemodynamically stable, and able to take oral medications
can be switched to oral therapy. If the pathogen has been identified, the choice of antibiotic for oral
therapy is based upon the susceptibility profile for that organism. If a pathogen is not identified, the
choice of antibiotic for oral therapy is either the same antibiotic as the intravenous antibiotic, or an
agent in the same drug class, which achieves adequate lung penetration when administered orally.

Duration — The duration of therapy should be based upon the clinical response. The standard
duration of therapy in the past was 14 to 21 days in part because of a concern for difficult to treat
pathogens (eg, Pseudomonas spp). However, a shorter course could significantly reduce the amount of
antimicrobial drugs used in hospitals where the emergence of resistant pathogens is a concern.

The following studies found that short course treatment is effective:

A prospective, randomized, multicenter trial of 401 patients with VAP compared outcomes
following eight versus 15 days of treatment [56]. All patients underwent bronchoscopy for
quantitative cultures and were empirically treated with a combination of an antipseudomonal
beta-lactam plus either an aminoglycoside or a fluoroquinolone. Investigators were encouraged
to change the regimen to a pathogen-directed treatment based upon culture results.

There was no significant difference between patients treated for eight compared to 15 days in
mortality or recurrent infection at 28 days; as expected, patients treated for eight days had
more antibiotic-free days. Among patients who developed recurrent infections, MDR pathogens
were isolated less frequently in those treated for eight days (42 versus 62 percent for those
treated for 15 days). However, patients with VAP caused by nonfermenting gram-negative
bacilli (eg, Pseudomonas spp) had a higher pulmonary infection recurrence rate when treated
for eight versus 15 days (41 versus 25 percent with 15 days of treatment), although mortality
was not different. In a subanalysis of 125 patients who had S. aureus isolated as a pathogen,
there was no significant difference based on treatment duration (8 or 15 days) for 28-day
mortality or VAP recurrence; this was also the case when only VAP caused by MRSA was
considered [57].

9 de 19 15/04/2011 07:30 p.m.


An ICU study evaluated clinical outcomes, including duration of treatment, following
implementation of a clinical guideline for the treatment of VAP compared to historical controls
(patients with VAP treated prior to implementation of the guideline) [58]. The clinical guideline
group had a shorter duration of antimicrobial therapy and was less likely to have a recurrent
episode of VAP.

A prospective study evaluated the ability of the Clinical Pulmonary Infection Score (CPIS) to
determine the duration of therapy for ICU patients with new pulmonary infiltrates (table 1)
[59]. Patients were included in the study if they had new-onset pulmonary infiltrates and a CPIS
<6. The patients were randomized to either a control group (standard therapy) or to the
experimental group (intravenous ciprofloxacin 400 mg every eight hours for three days).

The CPIS was reevaluated at three days and in patients with a CPIS <6, antibiotics were
discontinued in the experimental group. If the CPIS was >6, ciprofloxacin was continued or
antibiotics were changed based upon the microbiologic results. Significantly more patients in the
control group received antibiotics beyond three days compared to those in the experimental
group (90 compared with 28 percent in the experimental group). In addition to reduced
antibiotic use, the experimental group was less likely to have colonization/infection with
resistant organisms (15 compared with 35 percent of patients in the control group) and had a
trend towards lower mortality.

In a separate prospective cohort study of 312 patients who were treated with empiric antibiotics
in an ICU, investigators sought to determine if the CPIS score could be used to decrease the
amount or duration of antibiotic therapy [60]. The CPIS score was compared to the assessment
of a "pneumonia committee" (PC), which was comprised of investigators and clinicians
experienced in the management of ICU patients. The CPIS score had a reasonable predictive
value, but assessment by the PC and the CPIS score often diverged when the CPIS score was six
or less. Half of the empiric antibiotic use was for patients in whom pneumonia was suspected
but the PC or the CPIS score indicated that pneumonia was unlikely.

Recommendations — Based upon these data, we recommend that all patients with HAP, VAP, or
HCAP should be evaluated after 72 hours of initial empiric antimicrobial therapy.

If the patient has improved after 72 hours, and a pathogen is isolated, antimicrobial therapy should
be changed to a pathogen-directed regimen based upon the susceptibility pattern. Therapy should
generally be continued to complete a total course of 7 days; we would treat up to 15 days if P.
aeruginosa were the etiologic agent, and for up to 21 days for MRSA, depending upon the extent of
infection and clinical course [16]. Based on the study of S. aureus VAP discussed above, 8 days of
therapy may be adequate if there is good clinical response early in the course of appropriate therapy
[57]. If the patient has improved and no pathogen is identified, we would narrow the regimen,
discontinuing therapy for Pseudomonas spp and MRSA.

If the patient has not improved at 72 hours and a resistant pathogen is identified, therapy should be
changed to pathogen-directed treatment based upon the susceptibility pattern. In addition, failure to
improve at 72 hours should prompt a search for infectious complications, other diagnoses, or other
sites of infection.

PROGNOSIS — Despite high absolute mortality rates in HAP patients, the mortality attributable to
the infection is difficult to gauge. Many studies have found that HAP is associated with significant
excess risk of death. However, many of these critically ill patients die from their underlying disease
and not from pneumonia. Case-control studies estimate that the all-cause mortality rate for HAP and
VAP is in the range of 33 to 50 percent [2].

10 de 19 15/04/2011 07:30 p.m.


In a retrospective cohort study that used a large inpatient database, mortality rates were 10 percent
in patients with CAP, 19 percent in patients with HAP, 20 percent in patients with HCAP, and 29
percent in patients with VAP [61]. In another study, HCAP was associated with a higher in-hospital
mortality rate than CAP (18 versus 7 percent) [9].

Variables associated with increased mortality include [2,62-69]:

Serious illness at the time of diagnosis (eg, high APACHE score, shock, coma, respiratory
failure, ARDS)

Bacteremia

Severe underlying comorbid disease

Infection caused by an organism associated with multidrug resistance (Pseudomonas
aeruginosa, Acinetobacter spp)

Multilobar, cavitating, or rapidly progressive infiltrates on lung imaging

Delay in the institution of effective antimicrobial therapy

The Acute Physiology and Chronic Health Evaluation II (APACHE II) score has been considered the
best system to predict mortality in patients with VAP. A group of investigators has developed a
simpler scoring system to predict mortality: the IBMP-10 score based on the presence of
immunodeficiency; blood pressure <90 mm Hg systolic; multilobar infiltrates; platelet count
<100,000; and >10 days in hospital prior to onset of VAP [69]. Based on a point for each variable,
the mortality rates for each score were: 0 to 2 percent; 1 to 9 percent; 2 to 24 percent; 3 to 50
percent; 4 to 67 percent. In a preliminary analysis, the authors indicated that this five-point system
was comparable to APACHE-II in its ability to predict mortality in such patients.

SUMMARY AND RECOMMENDATIONS

The choice of the antibiotic treatment regimen for HAP, VAP, and HCAP should be influenced by
the patient's recent antibiotic therapy (if any), the resident flora in the hospital or intensive
care unit, the presence of underlying diseases, available culture data (interpreted with care),
and whether the patient is at risk for MDR pathogens. (See 'Treatment' above.)

For empiric coverage of HAP, VAP, and HCAP in patients with no known risk factors for
multidrug-resistant (MDR) pathogens, we suggest one of the following intravenous antibiotic
regimens:

Ceftriaxone (2 g intravenously daily)
Ampicillin-sulbactam (3 g intravenously every six hours)
Levofloxacin (750 mg intravenously daily) or moxifloxacin (400 mg intravenously daily).
When the patient is able to take oral medications, either agent may be administered orally
at the same dose as that used for IV administration.
Ertapenem (1 g intravenously daily) .
Choice of a specific agent for empiric therapy should be based upon knowledge of the
prevailing pathogens (and susceptibility patterns) within the healthcare setting. If there is
concern for gram-negative bacilli resistant to the above options (eg, Enterobacter spp,
Serratia spp, Pseudomonas spp) based upon microbiologic data at the specific institution, we
feel that it is reasonable to initiate piperacillin-tazobactam (4.5 g IV every six hours) or
another agent (eg, cefepime or a carbapenem) as monotherapy for patients without known

11 de 19 15/04/2011 07:30 p.m.


risk factors for MDR bacteria provided that the institution’s susceptibility data support in
vitro activity. (See 'No known MDR risk factors' above.)

For empiric coverage of HAP, VAP, and HCAP in patients with known risk factors for MDR
pathogens, we recommend empiric combination therapy including:

One of the following:

Antipseudomonal cephalosporin such as cefepime (2 g intravenously every eight hours) or
ceftazidime (2 g intravenously every 8 hours)
Antipseudomonal carbapenem such as imipenem (500 mg intravenously every six hours) or
meropenem (1 g intravenously every eight hours) or doripenem (500 mg intravenously
every eight hours; administered over one hour for HAP or HCAP, administered over four
hours for VAP)
Piperacillin-tazobactam (4.5 g intravenously every six hours)
For patients who are allergic to penicillin, the type and severity of reaction should be
assessed. If a skin test is positive or if there is significant concern to warrant avoidance of a
cephalosporin or carbapenem, aztreonam (2 g intravenously every six to eight hours) is
recommended.
Patients with past allergic reactions to cephalosporins may also be treated with aztreonam,
with the possible exception of those allergic to ceftazidime. Ceftazidime and aztreonam have
similar side chain groups, and cross reactivity between the two drugs is variable. The
prevalence of cross-sensitivity has been estimated at <5 percent of patients, based upon
limited data. Patients with past reactions to ceftazidime that were life-threatening or
suggestive of anaphylaxis (involving urticaria, bronchospasm, and/or hypotension) should
not be given aztreonam unless evaluated by an allergy specialist. In contrast, a reasonable
approach in those with mild past reactions to ceftazidime (eg, uncomplicated maculopapular
rash) would involve informing the patient of the low risk of cross-reactivity and
administering aztreonam with a graded challenge (1/100, 1/10, full dose, each separated by
1 hour of observation). (See "Cephalosporin-allergic patients: Subsequent use of
cephalosporins and related antibiotics", section on 'Use of carbapenems and monobactams'.)

PLUS one of the following:

Antipseudomonal fluoroquinolone, such as ciprofloxacin (400 mg intravenously every eight
hours) or levofloxacin (750 mg intravenously daily).
Aminoglycoside such as gentamicin or tobramycin (7 mg/kg intravenously once daily ) or
amikacin (20 mg/kg intravenously once daily ). The aminoglycoside can be stopped after five
to seven days in responding patients.

PLUS one of the following (if MRSA is suspected, there are MRSA risk factors, or there is a high
incidence of MRSA locally):

Linezolid (600 mg intravenously every 12 hours; may be administered orally when the
patient is able to take oral medications)
Vancomycin (15 to 20 mg/kg [based on actual body weight] intravenously every 8 to 12
hours for patients with normal renal function, with a target serum trough concentration of
15 to 20 mg/L.) In seriously ill patients, a loading dose of 25 to 30 mg/kg can be used to
facilitate rapid attainment of the target trough concentration. (See 'Known MDR risk
factors' above.)

12 de 19 15/04/2011 07:30 p.m.


Critical to reducing overuse of antimicrobials, "deescalation" of therapy should be considered
after 48 to 72 hours of initial therapy, and should be based upon the results of initial cultures
and the clinical response of the patient. (See 'Duration' above.)

The duration of therapy should be based upon the clinical response. A short duration of therapy
(eg, seven days) is sufficient for most patients with uncomplicated HAP, VAP, or HCAP who have
had a good clinical response. (See 'Duration' above.)

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16 de 19 15/04/2011 07:30 p.m.


GRAPHICS

Single-dose aminoglycoside nomogram

Nomogram showing the relationship between serum gentamicin or
tobramycin concentrations and time beginning at six hours after a
single dose of 7 mg/kg. The interval for drug administration varied
with estimated creatinine clearance (Ccr): every 24 hours at a Ccr
≥60 mL/min; every 36 hours at a Ccr of 40 to 59 mL/min; and
every 48 hours at a Ccr of 20 to 39 mL/min. Reproduced with
permission from: Nicolau, D, Quintiliani, R, Nightingale, CH. Once-daily
aminoglycosides. Conn Med 1992; 56:561. Copyright © 1992 Connecticut State
Medical Society.

17 de 19 15/04/2011 07:30 p.m.


Clinical Pulmonary Infection Score (CPIS)

Temperature
≥36.5 or ≤38.4 = 0 point

≥38.5 or ≤38.9 = 1 point

≥39 or <36.5 = 2 points

Blood leukocytes, microL
≥4000 or ≤11,000 = 0 points

<4000 or >11,000 = 1 point

Band forms ≥50 percent = add 1 point

Tracheal secretions
Absence of tracheal secretions = 0 point

Presence of non-purulent tracheal secretions = 1 point

Presence of purulent tracheal secretions = 2 points

Oxygenation
PaO2/FIO2, mmHg >240 or ARDS (defined as PaO2/FIO2 ≤200, PAWP ≤18 mmHg and acute
bilateral infiltrates) = 0 points

PaO2/FIO2 ≤240 and no ARDS = 2 points

Pulmonary radiography
No infiltrate = 0 point

Diffuse (patchy) infiltrate = 1 point

Localized infiltrate = 2 points

Progression of pulmonary infiltrate
No radiographic progression = 0 point

Radiographic progression (after HF and ARDS excluded) = 2 points

Culture of tracheal aspirate
Pathogenic bacteria cultured in rare or few quantities or no growth = 0 point

Pathogenic bacteria cultured in moderate or heavy quantity = 1 point

Same pathogenic bacteria seen on Gram's stain, add 1 point

Total (a score of >6 was considered suggestive of pneumonia)

ARDS: acute respiratory distress syndrome; HF: heart failure; PAWP: pulmonary arterial wedge pressure.
An initial score is based upon the first five variables. The last two variables are assessed on day 2 or 3.
Adapted with permission from: Singh, N, Rogers, P, Atwood, CW, et al. Short-course empiric antibiotic therapy
for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate
antibiotic prescription. Am J Respir Crit Care Med 2000; 162:505. Copyright © 2002 American Thoracic
Society.

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